Dehydrated hydrogel precursor-based, tissue adherent compositions and methods of use

ABSTRACT

Compositions and methods are provided for forming tissue-adherent hydrogels using substantially dry precursors. The dehydrated precursors are premixed prior to in situ therapy and utilize naturally-occurring body fluids as an aqueous environment that initiates transformation, which causes dissolution and nearly simultaneous crosslinking of the precursors, thus forming an insoluble hydrogel implant. The dehydrated precursor-based hydrogels may be used as sealants for fluid leaks from tissue, as adherent drug delivery depots, as means for augmenting and/or supporting tissue, and as means for serving a variety of other useful medical and surgical purposes.

FIELD OF THE INVENTION

This invention relates to hydrogels used as sealants for tissue fluidleaks, as adherent drug delivery depots, as means for augmenting and/orsupporting tissue, and as means for serving a useful medical or surgicalpurpose. More particularly, the present invention relates tocompositions and methods for forming tissue adherent hydrogels usingsubstantially dry precursors.

BACKGROUND OF THE INVENTION

In situ therapy has primarily focused on transformation of precursorsolutions into solids within a patient's body. Transformations have beenachieved by a variety of means, including precipitation, polymerization,crosslinking, and desolvation. Precursor materials may be natural orsynthetic, or a combination thereof. Examples of solution-based in situtherapy techniques include U.S. Pat. Nos. 4,804,691; 5,122,614;5,410,16; 4,268,495; 5,527,856; 5,614,204; 5,733,950; and 5,874,500.

Significant limitations exist when using solutions for in situ therapy.Solutions of low viscosity may flow away and be cleared from anapplication site before transformation and solidification occurs.Furthermore, formulation of the solutions may be complex, as preparationof precursor solutions typically requires reconstitution of theprecursors, or, when the solutions are stored frozen, thawing.

Polymerizable powdered mixtures have been combined with liquidinitiators to form settable pastes for use as bone cements, as discussedin U.S. Pat. Nos. 4,456,711; 5,468,811; and 4,490,497. However, allthese compositions and related methods for making medically-usefulproducts from such compositions are limited by use of a non-aqueoussolvent or initiator. Polymerizations are not activated by the presenceof aqueous physiological surroundings.

A variety of applications exist for in situ therapy. During surgery, forexample, tissues and organs may be damaged or traumatized, and maythereby develop leaks. Furthermore, the organs may be too fragile tomanipulate and repair using conventional surgical means, such assuturing. In situations where leaks appear or where conventionalsurgical management is difficult, surgical adhesives and sealants may beuseful.

Several tissue sealants are known in the art. The most commonly usedbiologically-based sealant is fibrin glue or fibrin sealant. Thissealant typically comprises aqueous solutions of purified fibrinogen andthrombin. A coagulum is formed by mixing these two solutions together,and the coagulum may serve as a sealant or tissue adhesive. However,adhesion strength is limited, and setup time may be long. Furthermore, awound leaking fluids is likely to wash the sealant away from anapplication site prior to solidification of the coagulum, therebylimiting the efficacy of fibrin glue. Likewise, the efficacy of allliquid sealants is limited by adherence of liquid sealants to tissuesurfaces that present liquid interfaces. It therefore becomes importantto have substantially dry surfaces prior to application of liquid tissuesealants. However, creation of dry application sites in situ is oftenunfeasible during surgery.

A product under the brand name Tachocomb (Behringwerke, Germany) hasrecently been introduced, which uses dry components to form a hemostaticpatch of the fibrin sealant. The patch has been formed using horsecollagen, bovine thrombin, and human fibrinogen. Since the componentmaterials are procured from animal sources, allergic responses anddisease transmission may result. The materials are also expensive tomanufacture. Furthermore, the efficacy of fibrin-based sealants may beadversely affected by anticoagulants routinely administered as part ofsurgical and interventional procedures.

More recently, synthetic alternatives to fibrin sealants have beendeveloped. One such material comprises photoactivated poly(ethyleneglycol) (“PEG”), which is marketed as FocalSeal™ (Focal, Inc.,Lexington, Mass.). Focal, Inc., claims that FocalSeal™ provides superiorstrength characteristics over fibrin sealants and glues. However, use oflight to initiate polymerization limits applicability in surgicalenvironments where bleeding is not effectively controlled, since bloodimpedes light transmission. Other surgical sealants, including syntheticsealants such as Co-Seal™, are marketed by Cohesion Technologies (PaloAlto, Calif.). However, these sealants, as well as FocalSeal™, require adry surface for application.

In view of the drawbacks associated with previously-known methods andapparatus for in situ therapy, it would be desirable to provide methodsand apparatus that overcome these drawbacks.

It further would be desirable to provide methods and apparatus that usedry materials procured from sources other than non-human animals.

It still further would be desirable to provide methods and apparatus forin situ therapy that are activated solely by the presence of aqueousphysiological surroundings.

It further would be desirable to provide methods and apparatus that donot require complex formulation prior to use.

It would also be desirable to provide methods and apparatus that remaineffective in the presence of anticoagulants.

It would be desirable to provide methods and apparatus for in situtherapy that are inexpensive to manufacture and are highly effective inclinical practice.

SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the present invention toprovide methods and apparatus for in situ therapy that overcomedrawbacks associated with previously-known methods and apparatus.

It is also an object of the present invention to provide methods andapparatus that use dry materials procured from sources other thannon-human animals.

It is another object to provide methods and apparatus for in situtherapy that are activated solely by the presence of aqueousphysiological surroundings.

It is yet another object to provide methods and apparatus that do notrequire complex formulation prior to use.

It still further is an object of the present invention to providemethods and apparatus that remain effective in the presence ofanticoagulants.

It is an object of the present invention to provide methods andapparatus for in situ therapy that are inexpensive to manufacture andare highly effective in clinical practice or field use, such as a battlefield where rapid medical attention may be needed.

These and other objects of the present invention are accomplished byproviding compositions and methods for forming tissue-adherent hydrogelsusing substantially dry precursors. The dehydrated hydrogel precursorsare premixed prior to in situ therapy and utilize naturally-occurringbody fluids as an aqueous environment that initiates transformation. Theprecursors do not form an insoluble, crosslinked solid until such timeas they are exposed to the aqueous physiological setting. Upon exposureto the aqueous setting, dissolution and nearly simultaneous crosslinkingof the dehydrated precursors occurs, thus forming an insoluble hydrogelimplant. The implant is preferably bioabsorbable.

The dehydrated precursor-based hydrogels of the present invention may beused for a variety of medical applications, including use as sealantsfor fluid leaks from tissue, as adherent drug delivery depots, and asmeans for augmenting and/or supporting tissue. The hydrogels aretypically a mixture of two or more individual dry precursors. Theprecursors may be selected for specific therapeutic uses, for example,adherence, coagulation of blood, dessication, etc. The precursors may beadministered directly to an open wound site or may be dispensed using ameans of application. The means of application may include, for example,a non-adhesive backing material, an absorbable backing material, asyringe applicator, a powder atomization or aerosolization system, or aneedle-less injector.

When used as a sealant and applied to a wound site, rapid uptake ofblood or other tissue fluid occurs, thereby facilitating crosslinking ofthe dehydrated precursor components and providing adherence of theresulting coagulum to underlying tissue. Additionally, active agents maybe added to the precursors to further promote the sealing process. Ahigh concentration of these active agents may be provided at a woundsite.

The dry precursors of the present invention may also be delivered totarget organs, such as a patient's lungs, by atomization of a finelymicronized mixture. Contact with tissue fluids results in crosslinkingand coating of mucosal tissues, thus providing an efficient means fordrug delivery.

Exemplary compositions and methods of use in accordance with the presentinvention are provided hereinbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects and advantages of the present invention willbe apparent upon consideration of the following detailed description,taken in conjunction with the accompanying drawings, in which:

FIG. 1 is an isometric view of non-adhesive backing materials for use asa delivery system for sealants of the present invention;

FIG. 2 is an isometric view of a syringe for use as a delivery systemfor the sealants of the present invention;

FIG. 3 is an isometric view of a powder atomizer delivery system;

FIG. 4 is an isometric view of a previously known aerosolizing deliverysystem for use with the sealants of the present invention;

FIG. 5 is an isometric view of a previously known needle-less injectordelivery system for use with the sealants; and

FIG. 6 is a side view of a previously known pneumatic injector deliverysystem.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides medical sealant compositions that are ina substantially dry form. The compositions typically comprise a mixtureof two or more individual dehydrated precursors, which activate uponexposure to fluid in a physiological environment. Upon exposure,dissolution and nearly simultaneous crosslinking of a composition'sdehydrated precursors occurs, thus forming an insoluble hydrogelimplant, which is preferably biodegradable. The hydrogels of the presentinvention may be used for a wide variety of medical applications,including use as sealants for fluid leaks from tissue, as adherent drugdelivery depots, and as means for augmenting and/or supporting tissue.They may be administered directly to an open wound site or may bedispensed using a means of application, for example, a non-adhesivebacking material, an absorbable backing material, a syringe applicator,a powder atomization or aerosolization system, or a needle-lessinjector, each of which is described in greater detail hereinbelow.

In a first embodiment, the precursors used for in situ gelation maycomprise a lyophilized, or freeze-dried form, wherein lyophilization hasbeen conducted on aqueous or organic solvents. Lyophilizationadvantageously provides very high surface area powders. Individuallyophilized precursors may then be compounded together or may be layeredon top of each other, for example, in a corrugated sheet fashion.Corrugated structure is expected to advantageously promote interlockingof precursor layers. The layers may comprise components that interactwith each other to form a crosslinked matrix. The crosslinks themselvesmay be physical or chemical in nature, or both.

As an example, a two-part dehydrated hydrogel precursor mixture mayconsist of an electrophilic, multifunctional poly(ethylene glycol)(“PEG”) precursor and a multifunctional, nucleophilic PEG precursor.These two dehydrated components may be compounded together when dry.Upon exposure to an aqueous environment, rapid chemical crosslinkingoccurs and forms a hydrogel that is adherent to tissue.

As another example, a fully-synthetic, solid PEG particulate hydrogelcomposition may be provided that has application, for example, inhemostasis and/or space-filling procedures. A degradable PEG hydrogel isfabricated, then dried or lyophilized. The lyophilized hydrogel ispulverized to a particulate size configured for use with a givendelivery system and treatment space.

The particulate composition may be fabricated as follows: first, thedegradable hydrogel is made and pulverized by methods known to those ofskill in the art, for example, by the methods described in Example 6hereinbelow. The hydrogel is then treated to provide synthetic organicfunctional groups on its surface that either directly react with bloodproteins or that are derivatized with other functional groups that reactwith proteins present in blood. For example, the hydrogel may be treatedto provide an abundance of carboxylate groups on its surface. Thesecarboxylate groups may be coupled using dicyclohexylcarbodiimide withgroups such as N-hydroxysuccinimide (“NHS”). The particulate compositionwith NHS surface derivatization may then be prepared and packaged in anappropriate manner, such as lyophilization.

In use, the composition may be applied into a body space to form adegradable hydrogel. Upon hydration with water in blood, the lyophilizedhydrogel swells, thereby partially or completely filling the space. Insurface treatment applications, the surface of the space is morecontiguously covered. The surface groups, once hydrated, becomeactivated and react with blood proteins, resulting in a layer or filledspace that is biocompatible, bioresorbable, and achieves hemostasis.

Free radical polymerization of lyophilized precursors may furtherfacilitate chemical crosslinking by providing ethylenically unsaturatedand substantially water soluble molecules containing necessary chemicalinitiators in dehydrated form. For example, polyalkylene oxide-based(meth)acrylated precursors may be used with redox initiators, such ast-butyl hydroperoxide and ferrous gluconate, dispersed within thepolymeric mix. Upon contact with moisture, the co-initiating system isactivated to produce free radicals that initiate crosslinking of themultiacrylated precursor to form a final implant. Several other watersoluble macromers and initiating systems may be useful for thisinvention and will be apparent to those of skill in the art of polymerchemistry. In addition to free radical polymerization, mechanisms forchemical crosslinking include condensation polymerization, anionic orcationic polymerization, and step growth polymerization.

Similarly, physical crosslinking may be utilized with lyophilizedprecursors. Mechanisms for physical crosslinking include ionicinteractions, hydrophobic interactions, hydrogen bonding, Van der Waalsforces, and desolvation. For example, a composition consisting of analginate precursor mixed with a calcium chloride precursor forms ioniccrosslinks in the presence of an aqueous environment.

In an alternative embodiment in accordance with the present invention,the precursors may be formed using spray drying to form granules ofpre-determined and controlled size. These granules optionally may becoated with a water dispersible or water soluble binding agent. Thebinding agent may comprise any of a number of water soluble or waterdispersible, low melting point (preferably between 37-50° C.)substances. The binding agent is expected to help maintain a pre-definedconfiguration, such as a sheet or a cone or larger composite granules,by, for example, stacking the coated precursors in a desiredconfiguration and then performing a brief treatment step, such asheating, to stabilize the desired configuration. This secondaryprocessing step is expected to provide shapes of sealant devicestailored for specific surgical settings. For example, a conical shapemay facilitate penetration of wounds, a sheet shape may be useful inabrasion-type lesions, etc.

Structures and additives that enhance fluid uptake into the dehydratedhydrogel precursors advantageously may be used in accordance with theprinciples of the present invention. For example, introduction ofmacroporosity into the structure of a shaped article formed fromdehydrated precursors is expected to enable a rapid uptake of a fluid,such as blood. Rapid uptake facilitates drying in a surgical field andthus creates a good substrate for adherence. It also enables more rapidfusion of the precursors to form the hydrogel. Additives that enhanceosmolarity of the hydrogel precursors can also be used to furtherenhance uptake of aqueous fluids. The additives may, for example,include salts, mannitol, sucrose, or other sugars. Substances that arenaturally occurring within the body are preferred.

Referring now to FIG. 1, non-adhesive backing materials 10 optionallymay be used with both the lyophilized and the spray dried sealants ofthe present invention. Backing materials 10 are preferablynon-absorbable in nature to allow convenient application of dehydratedsealants to tissue, so as to prevent, for example, the surgeon's glovefrom becoming adherent to the sealant patch. Materials such aspolytetrafluoroethylene, polyethylene, polyurethane, and silastic, amongothers, are expected to be useful for this purpose. Additionalnon-adhesive backing substrates may include silicone treated substrates.Also, coatings C optionally may be applied to backing materials 10 tohelp release the adhesive sealants from the backing materials, as wellas to enhance the non-adhesive nature of the sheets. Potential coatingmaterials include, for example, low molecular weight PEG (<2000 Da),which has a waxy consistency; glycerol; fatty acids; and sugars.

In another alternative embodiment, a coating of dehydrated hydrogelprecursors may be formed. Where a first precursor is reactive with asecond precursor during deployment of the device, a coating techniquemay be employed to deposit separable layers of the precursors. This maybe achieved by proper selection of a solvent system and coatingconditions such that, after deposition of a first layer of the firstprecursor, a second layer of the second precursor is deposited in such amanner as not to be reactive with the first precursor. In a stillfurther alternative embodiment, the precursors may be provided in asolvent that is inert to interaction between the dry precursors.

The sealant compositions of dehydrated hydrogel precursors may bedelivered using several delivery systems that are known in the medicaland pharmaceutical art. For example, the hydrogels may be deliveredusing pre-filled syringe 20 of FIG. 2, or using gas powered powderatomizer 30 of FIG. 3, such as is used for delivering talcum powder insurgical applications. Other means for delivery are also envisioned,including aerosolizing apparatus, such as apparatus 40 of FIG. 4 that isbeing developed by Inhale Therapeutics or an alternative system beingdeveloped by the Aradigm Corp. Pneumatic, needle-less injectors, such asapparatus 50 of FIG. 5 marketed by Powderject Ltd. (U.K.), are alsoexpected to facilitate delivery.

Pneumatic injectors for delivering medications, especially fluentmedications, without needles have been known for many years and arecommercially available. For example, the Bioject Corporation (Portland,Oreg.) markets apparatus 60 of FIG. 6 under the trade name “Biojector2000”. Apparatus 60 allows needle-less injection of a wide range offluent medications. More recently, pneumatic injection of powder-basedcompositions has been attempted, as illustrated by the Powderject systemof apparatus 50 of FIG. 5.

Pneumatic injectors may be actuated by a variety of techniques,including injection of a compressed gas; such as argon, carbon dioxide,nitrogen, or helium; and spring actuation. The injectors may bepartially or fully disposable, and often come packaged with a fillneedle or vial adaptor to draw medication or an implant-forming materialor solution from a vial into a syringe. The needle or vial adaptor isthen discarded and the filled syringe is inserted into the device. Aprotective cap is present over the syringe to prevent touchcontamination. In use, the syringe is inserted into the injector, theprotective cap is removed, and the injector is firmly placed against apatient's skin at an orthogonal angle. The injector is actuated andcontents of the syringe are delivered to the patient's tissue. Differentsyringe sizes provide different penetration depths within the tissue,including intradermal, subcutaneous, and intramuscular. In addition to areduction in transmission risk of blood borne pathogens, needle-lessinjectors provide a wider distribution of treatment materials, ascompared to standard hypodermic needles, which tend to deliver materialsin a localized bolus. However, delivery of solutions still is hamperedby rapid dissipation of the solutions from the site of administration.

In order to prolong the presence of treatment materials at theadministration site, it is desirable to entrap the therapeutic entity ordrug within an implant forming material. Thus, in situ implants formedusing needle-less injectors are expected to provide prolonged presenceat the administration site. This is expected to be useful in manyapplications, including genetic transfection, as well as delivery oftransformed cells, naked DNA, liposomes, microparticles, cationiccarriers complexed with DNA, viral vectors, and the like.

Further in accordance with the present invention, optional therapeuticagents may be added to the dehydrated sealants to create enhancedsealing efficacy or a locally adhesive depot for drug delivery. Forexample, incorporation of dehydrated human thrombin may lead to rapidcoagulation of bleeding when delivered by an adhesive patch formed fromthe sealant compositions described above.

Additional wound healing capabilities may be imparted to these adhesivepatches by incorporation of bioactive species. For example,anti-infective agents may be incorporated into patches used at abscesssites, bone growth factors may be incorporated into patches used at ornear fracture sites, and angiogenic factors, such as VEGF and FGF, maybe incorporated into patches used to stimulate blood vessel growth.Similarly, anti-angiogenic factors may be incorporated into patchesapplied at areas of tumor resection, to enable eradication of residualtumor cells from incomplete resection margins. Further therapeuticagents may include, for example, a wide variety of factors, proteins,peptides, oligonucleotides, genes, polysaccharides, proteoglycans,glycosaminoglycans, microparticles, and drugs, preferably of lowmolecular weight.

Advantageously, sealants of the present invention, created from dryprecursors, may be provided as convenient single-pack kits, or aspatches used as single units for each surgical defect. This is expectedto decrease formulation time and provide more efficient utilization ofmaterials, as compared to liquid surgical sealants.

In order to more fully describe various aspects of the presentinvention, a series of clinical examples are detailed below.

EXAMPLE 1

A dehydrated adhesive composition was formulated using two dehydratedhydrogel precursors. Precursor A consisted of 1 g poly(ethylene glycol)amine, and precursor B consisted of poly(ethylene glycol) extended withsuccinimidyl glutarate ester. The two precursors were mixed and groundtogether in a mortar and pestle until a smooth mixture was obtained.This mix was termed Mixture A. Mixture B was created like Mixture A, butwith additional incorporation of 500 Units of human thrombin to thecomposition.

A midline laparotomy was created in a 100 lb. hog under generalanesthesia. The hog was given 50 mg/Kg Heparin to induceanticoagulation. The hog's spleen was visualized. A scalpel was used tocreate a 2 cm long incision in 3 locations along the spleen. In thefirst location, 0.25 g of Mixture A was administered. In the secondlocation, 0.25 g of Mixture B was administered. In the third location,no further treatment was administered. All three locations werecompressed with gentle finger pressure and the time to hemostasis wasnoted. It was seen that hemostasis was obtained in Mixture A in 1 min,in Mixture B in 30 sec, and no hemostasis was obtained in the thirdlocation in 5 min.

EXAMPLE 2

The materials described in Example 1 were used in a rat liver resectionmodel. A midline laparotomy was created in a rat and its liver wasvisualized. A 1 cm longitudinal section was removed from each of threeliver lobes. 0.1 g of Mixture A and Mixture B were applied to the firstand second resections, respectively. The third site was left untreated.Time to hemostasis was noted. No further pressure was applied to thesites. The first site ceased bleeding in 45 seconds, the second site in15 seconds, and the third site was still seen to be bleeding after aperiod of 3 min.

EXAMPLE 3

A mixture of dehydrated precursors as described in Example 1 (e.g.,Mixture A) may be spray coated with N-vinyl caprolactam, which is in amelted state at 37° C. The coated precursors may then be placed over asheet of polyurethane backing material and smoothed out to form a 1 mmthick precursor layer. This layer of precursor briefly may be placed inan oven at 37° C. to fuse the precursors such that individual particlesstick together, but the composition retains an open porous structure.This dehydrated composite and the backing sheet may be cut to a desiredsize for convenient application. An additional layer or packing housingmay optionally be placed around the composition to prevent damage duringstorage and shipping.

EXAMPLE 4

A craniotomy was created in a dog in the temporal region. The dura wasexposed and a scalpel was used to create a 1 cm long dural defect, withthe help of a dural hook used to lift the dura. A gush of CSF wasvisually apparent as the arachnoid layer was cleaved. The durotomy wassutured shut using 8-0 Prolene suture. A valsalva maneuver thatincreases thoracic pressure to 40 cm of water was used to demonstrate acontinued leak of CSF from the dura. A dehydrated hydrogel precursorcomposite sheet as described in Example 3 was cut into a 2 cm×1 cm sizeand placed over the dural defect. Gentle pressure was applied over thenon-adhesive backing for about 30 sec. The seeping CSF was absorbed bythe precursor composite and resulted in formation of a contiguous andtissue adherent hydrogel patch that sealed the CSF leak.

EXAMPLE 5

10 g of PEG-Succinimidyl glutarate (M.W. 10,000 Da) may be mixed with400 mg of dilysine dihydrochloride, and the mixture may be groundovernight in a ball mill. The mixture may then be sieved to separatefine particles of less than 50 microns in size. These particles may beplaced in a powder atomizer cylindrical container having a volume ofabout 1 liter. At one end of the atomizer is a mouth piece, and at theother end is an assembly that provides rapid injection of a burst ofpressurized air in such a fashion that a dry mixture placed in thecylinder may be atomized and dispersed in the cylindrical chamber. Usingthe mouthpiece, the atomized precursor may be inhaled.

About 500 mg of the dehydrated mix may be combined with 200 mg of bovineinsulin to create a free flowing mix. This insulin-containing dehydratedmixture may be introduced in the cylindrical chamber described above,dispersed with the air injection, and inhaled by a diabetic patient.Upon contacting mucosal surfaces of the patient's bronchioles, themixture is expected to briefly dissolve and polymerize to form a thinhydrogel layer that entraps insulin and allows a slow delivery of thedrug over time. More efficient utilization and dosing of the drug withfewer side effects is expected. Furthermore, it is expected that a rangeof drugs including, for example, growth factors, genetic matter, andpainkillers may be easily delivered in this fashion.

EXAMPLE 6

10 g of a PEG-succinimidyl glutarate (“SG-PEG”) precursor, having amolecular weight of 20,849 Da, may be reacted with 193 mg of a trilysineprecursor. The SG-PEG precursor may be reconstituted in pH 4 phosphate,while the trilysine precursor may be reconstituted in pH 8 boratebuffer. The precursors are mixed and are applied as a coating to askived teflon sheet, using a draw down blade. The coated sheet is putinto a constant humidity chamber, such that the coating is allowed toreact and gel overnight at room temperature. During this time,aminolysis is completed, and amide bonds between amines of the trilysineprecursor and terminal carboxylate groups of the SG-PEG precursor areformed. Some hydrolysis of the formed gel may also occur at esterlinkages on the PEG side of the glutarate, resulting in free acid groupsthat are covalently attached to the gel. The concentration of these acidgroups may be controlled by controlling hydrolysis time, temperature,and pH, as is known in the art.

The hydrogel film may next be lyophilized to remove all water. Theresultant dry, solid film may be pulverized to an appropriateparticulate size. A slurry of the crosslinked, insoluble particulatehydrogel may then be prepared in an anhydrous organic solvent to whichdicyclohexylcarbodiimide (“DCC”) is added, followed byN-hydroxysuccinimide (NHS). The insoluble particles have thus beenderivatized with NHS groups. These are then dried, packaged, andsterilized in a manner appropriate with intended final use. Since theNHS may be coupled to the previously-free acid groups, dicyclohexylurea(“DCU”) may form, which is subsequently removed by repeated solventextraction steps.

Adhesive sealants and drug delivery systems as described in thisinvention provide a new modality of efficacious and economical sealants.Pulmonary delivery of such dehydrated hydrogel precursors mixed withtherapeutic compounds is expected to be an efficient and non-invasiveway of administering in situ therapy and controlled drug delivery.

Although particular embodiments of the present invention have beendescribed above in detail, it will be understood that this descriptionis merely for purposes of illustration. Further variations will beapparent to one skilled in the art in light of this disclosure and areintended to fall within the scope of the appended claims.

What is claimed is:
 1. A hydrogel system for in situ therapy comprisingan applicator associated with at least two substantially dry hydrogelprecursors for delivery to a common location, the dry hydrogelprecursors being water soluble and having functional groups for formingchemical crosslinks with each other at physiological pH to form ahydrogel in situ upon exposure to an aqueous fluid from a physiologicalenvironment.
 2. The hydrogel system of claim 1, wherein the dry hydrogelprecursors upon exposure to an aqueous physiological environment furtherform crosslinks that are physical in nature, the physical crosslinksbeing formed by a mechanism selected from the group consisting of ionicinteractions, hydrophobic interactions, hydrogen bonding, Van der Waalsforces and desolvation.
 3. The hydrogel system of claim 1, wherein thefunctional groups form chemical crosslinks by a mechanism selected fromthe group consisting of free radical polymerization, condensationpolymerization, anionic or cationic polymerization and step growthpolymerization.
 4. The hydrogel system of claim 1, wherein the chemicalcrosslinks are both chemical and physical in nature.
 5. The hydrogelsystem of claim 1, wherein the substantially dry hydrogel precursorscomprise a form chosen from the group consisting of lyophilized, spraydried, or in a solvent that is inert to interaction between the dryprecursors.
 6. The hydrogel system of claim 1, wherein the substantiallydry hydrogel precursors are compounded together prior to exposure to thefluid from the physiological environment.
 7. The hydrogel system ofclaim 5, wherein the substantially dry hydrogel precursors inlyophilized form comprise a corrugated structure.
 8. The hydrogel systemof claim 5, wherein the substantially dry hydrogel precursors in spraydried form comprise granules of controlled size.
 9. The hydrogel systemof claim 8, wherein the granules comprise a coating of a binding agentthat helps create a shaped article configuration.
 10. The hydrogelsystem of claim 9, wherein the hydrogel comprises a configuration chosenfrom the group consisting of a sheet, a cone, and a composite granule.11. The hydrogel system of claim 1, wherein the hydrogel precursors areadapted to form a hydrogel that is biodegradable.
 12. The hydrogelsystem of claim 1 wherein the applicator is chosen from the groupconsisting of a non-adhesive backing material, an absorbable backingmaterial, a syringe applicator, a powder atomization system, and aneedle-less injector.
 13. The hydrogel system of claim 12, wherein thenon-adhesive backing material is non-absorbable.
 14. The hydrogel systemof claim 13, wherein the non-adhesive backing material is fabricatedfrom a material chosen from the group consisting ofpolytetrafluoroethylene, polyethylene, polyurethane, and silastic. 15.The hydrogel system of claim 12, wherein the non-adhesive backingmaterial further comprises a coating, the coating configured tofacilitate release of the hydrogel from the non-adhesive backingmaterial.
 16. The hydrogel system of claim 15, wherein the coating isfabricated from a material chosen from the group consisting ofpoly(ethylene glycol) with a molecular weight less than 2000 Da,glycerol, fatty acid, and sugar.
 17. The hydrogel system of claim 1further comprising therapeutic agents in communication with the hydrogelprecursors.
 18. The hydrogel system of claim 17, wherein the therapeuticagents are chosen from the group consisting of thrombin, anti-infectiveagents, bone growth factors, angiogenic factors, anti-angiogenicfactors, growth factors, proteins, peptides, oligonucleotides, genes,polysaccharides, proteoglycans, microparticles, glycosaminoglycans, anddrugs.
 19. The hydrogel system of claim 1 wherein the hydrogel system isprovided in a form chosen from the group consisting of a kit and apatch.
 20. A method of forming a dehydrated precursor-basedwater-insoluble hydrogel medical implant in situ comprising: providingat least two substantially dry hydrogel precursors that are watersoluble and include functional groups that make chemical crosslinks toeach other to form the water-insoluble hydrogel medical implant whenmixed together in an aqueous environment at physiological PH; deliveringthe hydrogel precursors to an implantation site in situ in a patient;and exposing the precursors to aqueous physiological fluids atphysiological pH at the implantation site.
 21. The method of claim 20,wherein providing a hydrogel precursor comprises providing a hydrogelprecursor associated with a bioactive species.
 22. The method of claim20 further comprising using the hydrogel medical implant for deliveringdrugs.
 23. The method of claim 20, wherein forming the medical implantseals fluid leaks from the implantation site.
 24. The method of claim20, wherein forming the medical implant supports or augments theimplantation site.
 25. The method of claim 20, wherein delivering thehydrogel precursors to the implantation site comprises inhaling thehydrogel precursors.
 26. A method of forming hydrogel particulatescomprising: providing a hydrogel; removing water from the hydrogel;pulverizing the hydrogel to particulates of controlled size; andtreating the particulates to provide synthetic organic functional groupson a surface of the particulates, the functional groups configured toform chemical crosslinks with tissue and/or blood components.
 27. Themethod of claim 26 further comprising lyophilizing the particulates. 28.The method of claim 26, wherein providing synthetic organic functionalgroups comprises providing electrophilic groups on at least a portion ofthe particulates.
 29. The method of claim 28 wherein providing theelectrophilic groups comprises a step of providing N-hydroxysuccinimidegroups.
 30. The method of claim 26 further comprising applying theparticulates into a body space, thereby forming a bioreactive,degradable hydrogel in situ.
 31. The method of claim 30, wherein forminga bioreactive, degradable hydrogel in situ comprises: hydrating theparticulates, thereby causing the particulates to swell and partially orcompletely fill the body space; and reacting the particulates withtissue and/or blood components to form the biocompatible, degradablehydrogel.
 32. The hydrogel system of claim 1, wherein the functionalgroups include an electrophile and a nucleophile.
 33. The hydrogelsystem of claim 32 wherein at least one of the hydrogel precursorscomprises poly(ethylene) glycol and the electrophile or the nucleophile.34. The hydrogel system of claim 1, wherein the dry precursors arepowders.